Microbial Metabolic Pathways Guide Response to Immune Checkpoint Blockade Therapy
Cancer Discovery, vol. 16, pp. 95–113
Abstract
Studies have identified a link between specific microbiome-derived bacteria and immune checkpoint blockade (ICB) efficacy. However, these species lack consistency across studies, and their immunomodulatory mechanisms remain elusive. To understand the influence of the microbiome on ICB response, we studied its functional capacity. Using pan-cancer metagenomics data from ICB-treated patients, we showed that community-level metabolic pathways are stable across individuals, making them suitable for predicting ICB response. We identified several microbial metabolic processes significantly associated with response, including the methylerythritol 4-phosphate (MEP) pathway, which was associated with response and induced Vδ2 T cell-mediated antitumor responses in patient-derived tumor organoids. In contrast, riboflavin synthesis was associated with ICB resistance, and its intermediates induced mucosal-associated invariant T (MAIT) cell-mediated immune suppression. Moreover, gut metabolomics revealed that high riboflavin levels were linked to worse survival in patients with abundant intratumoral MAIT cells. Collectively, our results highlight the relevance of metabolite-mediated microbiome-immune cell cross-talk. SIGNIFICANCE: Microbial metabolic pathways are highly conserved across individuals and therefore offer an opportunity to link the microbiome to immunotherapy efficacy. We identified specific microbial metabolic pathways associated with response to ICB and provided mechanistic insights into the immunomodulatory influence of these pathways on antitumor immunity.
Authors 21
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The Netherlands Cancer Institute
Affiliation as printed
1Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
2Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
Netherlands Cancer Institute, Amsterdam, Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
1Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
2Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
3Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands
Netherlands Cancer Institute, Amsterdam, Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
1Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
2Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
Netherlands Cancer Institute, Amsterdam, Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
1Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
2Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
Netherlands Cancer Institute, Amsterdam, Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
1Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
2Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
Netherlands Cancer Institute, Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
1Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
2Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
1Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
2Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
Netherlands Cancer Institute, Amsterdam, Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
1Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
2Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
4Department of Pathology, Antoni van Leeuwenhoek/the Netherlands Cancer Institute, Amsterdam, the Netherlands
Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Baltimore, MD, United States
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The Netherlands Cancer Institute
Affiliation as printed
5Core Facility Molecular Pathology & Biobanking, the Netherlands Cancer Institute, Amsterdam, the Netherlands
Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
5Core Facility Molecular Pathology & Biobanking, the Netherlands Cancer Institute, Amsterdam, the Netherlands
Netherlands Cancer Institute, Amsterdam, Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
6Department of Biometrics, Netherlands Cancer Institute, Amsterdam, the Netherlands
Netherlands Cancer Institute, Amsterdam, Netherlands
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Utrecht University · The Netherlands Cancer Institute · University Medical Center Utrecht
Affiliation as printed
2Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
7Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
UMC Utrecht, Utrecht, Netherlands
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Utrecht University · The Netherlands Cancer Institute · University Medical Center Utrecht
Affiliation as printed
2Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
7Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
UMC Utrecht, Utrecht, Netherlands
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Utrecht University · The Netherlands Cancer Institute · University Medical Center Utrecht
Affiliation as printed
2Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
7Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
University Medical Center Utrecht, Utrecht, Utrecht, Netherlands
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University Medical Center Utrecht
Affiliation as printed
8Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands
University Medical Center Utrecht, Utrecht, Netherlands
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University Medical Center Utrecht
Affiliation as printed
8Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands
University Medical Center Utrecht, Utrecht, Netherlands
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Leiden University Medical Center
Affiliation as printed
9Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands
Leiden University Medical Center, Leiden, Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
1Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
2Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
Netherlands Cancer Institute, Amsterdam, Netherlands
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The Netherlands Cancer Institute · Delft University of Technology
Affiliation as printed
10Faculty of EEMCS, Delft University of Technology, Delft, the Netherlands
2Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
3Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands
The Netherlands Cancer Institute, Amsterdam, NH, Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
1Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
2Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
Netherlands Cancer Institute, Amsterdam, Netherlands
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